Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated β-Cell Death

  1. Mark Peakman1,6
  1. 1Department of Immunobiology, School of Medicine, King’s College London, London, U.K.
  2. 2Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
  3. 3Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, U.K.
  4. 4Laboratory of Immunobiology, Blood and Tissue Bank, Institut d’Investigacio Germans Trias i Pujol, Barcelona, Spain
  5. 5Department of Diabetes and Endocrinology, Guy’s & St Thomas’ Hospital National Health Service (NHS) Foundation Trust, London, U.K.
  6. 6National Institute for Health Research Biomedical Research Centre at Guy’s & St Thomas’ NHS Foundation Trust and King’s College London, London, U.K.
  7. 7Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
  8. 8Diabetes Research Group, School of Medicine, King’s College London, London, U.K.
  1. Corresponding author: Mark Peakman, mark.peakman{at}kcl.ac.uk.

Abstract

OBJECTIVE CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to β-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for β-cells.

RESEARCH DESIGN AND METHODS Peripheral blood CD4 T-cell responses to β-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat β-cells, and the rat insulinoma cell line INS-1E were examined.

RESULTS A total of 27 patients (54%) showed IL-17 reactivity to one or more β-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1β/interferon (IFN)-γ–induced and tumor necrosis factor (TNF)-α/IFN-γ–induced apoptosis in human islets, rat β-cells, and INS-1E cells, in association with significant upregulation of β-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-κB.

CONCLUSIONS Circulating IL-17+ β-cell–specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to β-cell death involving IL-17 and STAT1 and NF-κB, rendering this cytokine a novel disease biomarker and potential therapeutic target.

Footnotes

  • Received November 30, 2010.
  • Accepted May 5, 2011.

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  1. Diabetes vol. 60 no. 8 2112-2119
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